Mass spectrometry imaging (MSI) is increasingly used for a wide range of applications, from measuring distribution of metabolites within tissues sections to histology. Spatial resolutions typically range from few to hundreds of microns.
Two approaches are generally used to acquire an image of a flat sample.
One approach to MSI is that of rastering, as explained in U.S. Pat. No. 5,808,300. A narrow focused ionization beam (for example, a laser beam for MALDI, LAESI, LDI, etc., primary ion beam for SIMS, primary droplet beam for DESI, primary metastable beam for DART, etc.) is used to produce ions from a small spot to be analysed by a mass spectrometer. As a surface is rastered under the beam, individual pixels are probed sequentially and corresponding data are assembled into an image. This method allows high-resolution, high mass accuracy analysis (including multi-stage mass spectrometry or MSn) by a range of different types of mass spectrometers (TOF, FTICR, ORBITRAP™, linear trap stand-alone and hybrid instruments), sampling at atmospheric pressure and other advantages. Unfortunately, this rastering approach also has a significant disadvantage in that, since time of measurement is directly proportional to the number of pixels in the image, a scan might take many hours or even days. This greatly hinders the use of MSI in general analytical and industry practice.
To circumvent this limitation with the rastering approach, one possibility is to split the ionising beam into multiple beams with subsequent multiplexed MS analysis (U.S. Pat. No. 6,734,421 by Franzen). Alternatively, the image could be acquired first at a low spatial resolution (per the method disclosed in U.S. Pat. No. 7,655,476 by H. Bui) and then only areas of interest (for example, areas with highly differentiated analyte abundances) are sampled with high spatial resolution. However, these approaches do not allow a significant reduction in the measurement time.
As an alternative to rastering, a second approach to MSI is similar to the one used in optical imaging: acquisition of a panoramic spectrum using a 2D array of detectors. This approach takes its roots from position-sensitive detectors used in TOF (as shown e.g. in O. Jagutzki et al., Nucl. Instrum. Meth. Phys. Res. A, 477 (2002) 244-249) and 1D arrays (e.g. Z. Amitay and D. Zajfman, Rev. Sci. Instrum. 68 (3) (1997) 1387-1392) and capitalizes on the great advances in microelectronics over the last decades. A 65 kpixel TIMEPIX chip was presented in X. Llopart et al. Nucl. Instrum. Meth. Phys. Res. A 581 (2007) 485-494 and utilised for ion detection with a simple linear MALDI-TOF analyser in U.S. Pat. No. 8,274,045 and with a SIMS-TOF in A. Kiss et al., Rev. Sci. Instrum. 84, 013704 (2013). Though the chip allows for the possibility of acquiring tens of thousands pixels in parallel, temporal resolution of the current chip barely suffices for unit resolution up to moderate m/z (few hundreds) and does not allow resolution of isobaric interferences or effective identification of peaks. Also, the chip must operate in high vacuum as it uses microchannel plates (MCP) for conversion of incoming high-energy ions into electrons and electron multiplication. Further improvement of temporal resolution of electronics would improve mass resolution but inherent energy spread in laser ionization would allow further increase of mass resolution only at the expense of spatial resolution. This is clearly demonstrated by H. Hazama et al. in J. Biomed. Opt. 16(4), 046007 (2011) using multi-turn TOFMS of the MULTUM type to increase mass resolution where the image quality deteriorates rapidly with the increase of the number of turns.
The limitations of the rastering technique and the 2D array of detectors technique are addressed by the present invention.